Leucine supplementation modulates body composition and early weight rebound during GLP-1 receptor agonist therapy in diet-induced obese mice.

Abstract

Purpose: GLP-1 receptor agonists (GLP-1RAs) like semaglutide are effective for obesity treatment but may cause lean mass loss and post-discontinuation weight rebound. This study aimed to explore whether leucine supplementation alone or combined with semaglutide optimizes body composition in diet-induced obese (DIO) mice.

Methods: Male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity. Obese mice were then treated for 14 days with daily subcutaneous injections of semaglutide (120 µg/kg) or vehicle, along with either 1.5% leucine in drinking water or control water, and received the muscle-targeted mTORC1 inhibitor MTP-mTORC1i (1.5 mg/kg) or vehicle three times per week. Body weight, food intake, and body composition (assessed by EchoMRI) were monitored throughout this period. Following semaglutide withdrawal, leucine supplementation and MTP-mTORC1i administration were continued to evaluate their effects on weight rebound.

Results: Semaglutide combined with leucine induced greater fat mass loss and higher lean mass retention compared to semaglutide alone, without further suppressing appetite. Following semaglutide discontinuation, leucine supplementation significantly attenuated weight rebound, reduced fat rebound, and preserved lean mass. These beneficial effects were completely abrogated upon mTORC1 inhibition, underscoring the critical dependence on this signaling pathway.

Conclusions: Leucine supplementation may refine GLP-1RA-induced weight loss by favoring fat reduction and preserving lean mass, and could potentially alleviate post-discontinuation weight rebound through muscle mTORC1 activation. Given the relatively short 14-day intervention and limited post-withdrawal follow-up period, these findings should be regarded as preliminary. Leucine may represent a promising adjuvant strategy to improve obesity management, pending validation in longer-term clinical investigations.